Milk is the most abundant source of PTHrP in nature, and several studies have suggested that PTHrP from the mammary gland (MG) is released into the circulation during lactation. We hypothesize that the PTHrP produced by the lactating MG acts systemically to liberate skeletal calcium for milk production and locally to promote the transport of this calcium into milk. In order to test this hypothesis, we propose using the cre/lox recombinase system to generate mice in whom the PTHrP gene will be deleted only in mammary epithelial cells (MEC) only during late pregnancy and lactation. This approach will allow us to circumvent the developmental abnormalities associated with the traditional PTHrP knockout or "rescued knockout" mice, and will allow us to determine if mammary-derived PTHrP mobilizes calcium from the maternal skeleton. In addition to these experiments, in order to study if PTHrP directly affects the secretion of calcium into milk, we plan to make use of a novel system that recapitulates the lactating alveolus in vitro, to ask if PTHrP regulates calcium transport across MEC. We believe that the experiments outlined in this proposal will allow us to understand the function of PTHrP during lactation more fully.